ESPE Yearbook of Paediatric Endocrinology

Cell. 2021 Oct 28;184(22):5506–5526. doi: 10.1016/j.cell.2021.09.034

Brief Summary: The authors review the function and the underlying molecular mechanisms of 4 major species of endogenous cytoplasmic DNA (cytoDNA) in the development of chronic ageing-associated diseases.

In the presence of foreign DNA (e.g. viral infections), innate immunity acts as a defence mechanism that produces cytokines and chemokines to activate the inflammatory cell response. Key cellular sensors that trigger innate immune system signalling pathways and are responsible of recognizing external molecular patterns, including nucleic acids, are well known. For example, STING, a molecule that stimulates interferons, is important for the recognition of cytoDNA and enhances the expression of genes involved in the innate immune system that react to several DNA pathogens. In the absence of a pathogen, the presence of DNA in the cytoplasm is interpreted as toxic and the defences of the immune system are activated. This inflammatory reaction, called ‘sterile inflammation’, has been associated with cancer, ageing and neurodegenerative diseases, which are accompanied by a chronic level inflammation.

The role of endogenous cytoDNA in the activation of the innate immune system is well-known, but their contribution to the development of chronic diseases remains unclear. Studies of the function and the biological formation of the different cytoDNAs revealed similar potential mechanisms, such as the loss of nuclear membrane integrity for cytosolic accumulation of micronuclei and retrotransposons. It is suggested that further understanding of these processes might contribute to novel therapeutic opportunities in the treatment of related human disease.